Self & Other
17. mRNA, and What COVID Taught Us
In 1985, a young Hungarian biochemist named Katalin Karikó immigrated to the United States. She was thirty years old, she did not speak much English, and she was carrying her four-year-old daughter and a teddy bear in which she and her husband had hidden the equivalent of about a thousand dollars in currency, which was the largest sum it was legal to take out of Hungary at the time. She was on her way to a postdoctoral research position at Temple University in Philadelphia. She was, by any reasonable standard, starting over.
Karikó was interested in a molecule called messenger RNA — mRNA. The molecule itself was not exotic. Every cell in your body uses mRNA every minute of every day. When a gene needs to be read, the cell makes a temporary mRNA copy of the gene, ships the mRNA to the cell’s protein-making machinery, and the machinery uses the mRNA as a template to build the protein the gene encodes. This is how proteins get made. It is one of the most basic processes in biology, taught in every introductory class.
Karikó’s idea, which she had become attached to in graduate school, was that you could use mRNA as a medicine. If you could synthesize mRNA in the lab encoding any protein you wanted — a hormone, an enzyme, a viral antigen — and deliver it into a person’s cells, the cells would briefly make that protein themselves. The mRNA would degrade naturally within hours; the protein would last a few days. The entire effect would be temporary, controllable, and — in principle — applicable to almost any medical situation that called for a particular protein in the body.
Almost no one believed this would work.
The objections were technical and substantial. Synthetic mRNA, when injected into animals, triggered enormous inflammatory responses. The cells recognized it as foreign and attacked it before it could be translated. Even when small amounts got through, the protein they produced was unstable. The mRNA itself was extremely fragile and broke down within minutes outside a cell. The infrastructure for making mRNA at scale didn’t exist. The infrastructure for delivering it into human cells didn’t exist. There were a hundred reasons it wasn’t going to work, and the technology to address most of them did not yet exist either.
Karikó spent the next two decades trying to fix this, mostly alone, often without funding. She moved from Temple to the University of Pennsylvania. She wrote grants that did not get funded. She was demoted in 1995 because the grants were not coming in. She kept working. In 1997 she met an immunologist named Drew Weissman in the line at the photocopier at Penn, fell into conversation, and began a collaboration that would, eventually, solve the central problem.
The problem was that synthetic mRNA was being recognized as foreign by the immune system. Karikó and Weissman discovered, in a 2005 paper that almost no one initially noticed, that if you replaced one of the four building blocks of mRNA with a slightly modified version — specifically, replacing the nucleoside uridine with a chemical cousin called pseudouridine — the mRNA stopped triggering the inflammatory response and could enter cells, get translated, and produce protein without setting off alarms. The modification was small. The implications were enormous. It was the first technical step toward making mRNA a viable therapy.
The 2005 paper sat largely ignored for years. The companies that would eventually become BioNTech and Moderna licensed the technology in the late 2000s and early 2010s, and began the long, expensive, mostly unsuccessful work of trying to turn it into actual medicines. Karikó left Penn for BioNTech in 2013. By 2019, after fifteen years of refinement, the platform was working. mRNA could be synthesized in industrial quantities, packaged in microscopic spheres of fat called lipid nanoparticles that protected it and helped it enter cells, and delivered into animals and — in early trials for cancer and infectious disease — into people. It hadn’t yet produced an approved medical product. It was almost there.
Then, in late 2019, a new coronavirus emerged in China.
What happened over the next year is the chapter in this book that almost everyone reading it remembers. The story of why it happened that fast, and what it taught us, is what we will spend the rest of this chapter on.
What the Vaccines Are
In January 2020, the genetic sequence of the new coronavirus was posted online by Chinese researchers. Within hours, scientists at BioNTech and at Moderna independently used that sequence to design a piece of mRNA encoding the virus’s surface spike protein — the protein the virus uses to enter human cells.
The vaccine they designed is, as a matter of biology, simple to describe. The mRNA encodes one specific viral protein — not the virus, not anything that can replicate, just the recipe for one particular protein the virus wears on its surface. The mRNA is wrapped in lipid nanoparticles, the small spheres of fat developed over the previous decade. The whole package is injected into the muscle of the upper arm.
Once injected, the lipid nanoparticles fuse with the membranes of nearby cells. The mRNA enters those cells. The cells’ own ribosomes — the same ribosomes that have been making proteins for that person their entire life — read the mRNA and produce the spike protein. The spike protein is then displayed on the surface of those cells, in the MHC molecules we met in Chapter 6.